Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Prasugrel and ticagrelor have superior efficacy compared with clopidogrel in moderate CKD but have not been studied in kidney failure. The study objective is to determine the effectiveness and safety of prasugrel and ticagrelor in kidney failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:This retrospective cohort study used United States Renal Data System data from 2012 to 2015. We identified all patients on dialysis who received a drug-eluting stent and were alive at 90 days after stent implantation. Inverse probability-weighted Cox proportional hazard models were used. Weights were estimated with propensity scores for multiple treatments. RESULTS:=0.98). A numerically higher incidence of clinically relevant bleeding was seen with prasugrel or ticagrelor compared with clopidogrel (weighted hazard ratio, 1.15; 95% confidence interval, 0.95 to 1.38 and weighted hazard ratio, 1.13; 95% confidence interval, 0.91 to 1.40, respectively). CONCLUSIONS:Prasugrel or ticagrelor does not seem to be associated with significant benefits compared with clopidogrel in patients with kidney failure treated with drug-eluting stents. PODCAST/UNASSIGNED:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_04_02_CJN12120720.mp3.

BACKGROUND:People with type 2 diabetes and chronic kidney disease experience a high burden of hypertension, but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population are uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP-lowering therapy is also unknown. METHODS:The CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) randomized people with type 2 diabetes and chronic kidney disease to canagliflozin or placebo. In a post hoc analysis, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP-lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mm Hg while receiving ≥3 classes of BP-lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. RESULTS:interaction ≥0.35), as were effects on other key kidney, cardiovascular, and safety outcomes. CONCLUSIONS:In people with type 2 diabetes and chronic kidney disease, canagliflozin lowers systolic BP across all BP-defined subgroups and reduces the need for additional BP-lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP-lowering therapy in people with chronic kidney disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.

Background Coronary revascularization provides important long-term clinical benefits to patients with high-risk presentations of coronary artery disease, including those with chronic kidney disease. The cost-effectiveness of coronary interventions in this setting is not known. Methods and Results We developed a Markov cohort simulation model to assess the cost-effectiveness of percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) in patients with chronic kidney disease who were hospitalized with acute myocardial infarction or unstable angina. Model inputs were primarily drawn from a sample of 14 300 patients identified using the Medicare 20% sample. Survival, quality-adjusted life-years, costs, and cost-effectiveness were projected over a 20-year time horizon. Multivariable models indicated higher 30-day mortality and end-stage renal disease with both PCI and CABG, and higher stroke with CABG, relative to medical therapy. However, the model projected long-term gains of 0.72 quality-adjusted life-years (0.97 life-years) for PCI compared with medical therapy, and 0.93 quality-adjusted life-years (1.32 life-years) for CABG compared with PCI. Incorporation of long-term costs resulted in incremental cost-effectiveness ratios of $65 326 per quality-adjusted life-year gained for PCI versus medical therapy, and $101 565 for CABG versus PCI. Results were robust to changes in input parameters but strongly influenced by the background costs of the population, and the time horizon. Conclusions For patients with chronic kidney disease and high-risk coronary artery disease presentations, PCI and CABG were both associated with markedly increased costs as well as gains in quality-adjusted life expectancy, with incremental cost-effectiveness ratios indicating intermediate value in health economic terms.

Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.

Background/UNASSIGNED:There is a paucity of contemporary data examining electrolyte changes during and immediately after hemodialysis (HD), and their relationship with dialysate prescriptions. The present study examines these relationships. Methods/UNASSIGNED:We analyzed patient- (n=66) and HD session-level pre- and post-dialysis laboratory data (n=1,713) over a six-month period from the Monitoring in Dialysis Study. We fit mixed effects regression models to analyze electrolyte, blood urea nitrogen, creatinine, and albumin levels immediately post-HD, accounting for pre-HD and dialysate prescriptions. In a subset of US patients (n=40), 15-minute post-HD and 30-minute post-HD values were available at one session. Predictive models were fit to estimate electrolyte levels immediately post-HD, accounting for pre-HD concentrations and dialysate prescriptions. Results/UNASSIGNED:Serum bicarbonate, calcium, and albumin increased (mean increase 4.9±0.3 mEq/L, 0.7±0.1 mEq/L, and 0.4±0.03 g/dL, respectively), whereas potassium, magnesium, and phosphorus decreased immediately post-HD (mean -1.2±0.1 mEq/L, -0.3±0.03 mEq/L, and -3.0±0.2 mg/dL, respectively). Hypokalemia and hypophosphatemia were present in 40% of and 67% of immediate post-HD samples, respectively. Dynamic changes were observed in electrolyte concentrations at 15- and 30-minutes post-HD, compared to immediately post-HD. Conclusion/UNASSIGNED:We describe the magnitude of post-dialytic changes in serum electrolytes with contemporary HD, reporting a high incidence of electrolyte abnormalities post-HD, and present predictive nomograms relating electrolyte changes immediately post-HD to dialysate prescriptions. Our results may be useful for clinical care and provide insights for future research on dialysate prescriptions.

Introduction/UNASSIGNED:Reports from the United States suggest that acute kidney injury (AKI) frequently complicates COVID-19, but understanding of AKI risks and outcomes is incomplete. Additionally, whether kidney outcomes have evolved during the course of the pandemic is unknown. Methods/UNASSIGNED:We used electronic records to identify COVID-19 patients with and without AKI admitted to 3 New York Hospitals between March 2 and August 25, 2020. Outcomes included AKI overall and according to admission week, AKI stage, the requirement for new renal replacement therapy (RRT), mortality and recovery of kidney function. Logistic regression was utilized to assess associations of patient characteristics and outcomes. Results/UNASSIGNED:Out of 4732 admissions 1386 (29.3%) patients had AKI. Among those with AKI, 717 (51.7%) had Stage 1, 132 (9.5%) Stage 2, 537 (38.7%) stage 3, and 237 (17.1%) required RRT initiation. In March 536/1648 (32.5%) of patients developed AKI compared with 15/87 (17.2%) in August (P<0.001 for monthly trend) whereas RRT initiation was required in 6.9% and 0% of admission, in March and August respectively. Mortality was higher with than without AKI (51.6% vs 8.6%) and was 71.9% in individuals requiring RRT. However, most patients with AKI who survived hospitalization (77%) recovered to within 0.3 mg/dL of baseline creatinine. Among those surviving to discharge, 62% discontinued RRT. Conclusions/UNASSIGNED:AKI impacts a high proportion of admitted COVID-19 patients and is associated with high mortality, particularly when RRT is required. AKI incidence appears to be decreasing over time and kidney function frequently recovers in those who survive.

Background/UNASSIGNED:The intestinal microbiome is an appealing target for interventions in ESKD because of its likely contribution to uremic toxicity. Before conducting clinical trials of microbiome-altering treatments, it is necessary to understand the within-person and between-person variability in the composition and function of the gut microbiome in patients with ESKD. Methods/UNASSIGNED:We conducted a multicenter, nonrandomized, crossover feasibility study of patients on maintenance hemodialysis consisting of three phases: pretreatment (8 weeks); treatment, during which the prebiotic, p-inulin, was administered at a dosage of 8 g twice daily (12 weeks); and post-treatment (8 weeks). Stool samples were collected 1-2 times per week and blood was collected weekly for 28 weeks. The gut microbiome was characterized using 16S ribosomal-RNA sequencing and metabolomic profiling. Results/UNASSIGNED:=0.004) and a progressive decrease in prevalence of high intraclass correlations, indicating an increase in intraparticipant microbiome diversity during and after p-inulin treatment. An effect of p-inulin on the metabolomic profile was not evident. Conclusions/UNASSIGNED:The intraparticipant stability of the gut microbiome under no-treatment conditions, the tolerability of p-inulin, the signals of increased diversity of the microbiome with p-inulin treatment, and the willingness of participants to provide stool samples all support the feasibility of a larger trial to investigate interventions targeting the gut microbiome in patients with ESKD. Whether or not p-inulin has sufficient efficacy as an intervention requires evaluation in larger studies. Clinical Trial registry name and registration number/UNASSIGNED:Gut Microbiome and p-Inulin in Hemodialysis, NCT02572882.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS/METHODS:=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP. RESULTS:=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories. CONCLUSIONS:Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER/UNASSIGNED:ClinicalTrials.gov: CREDENCE, NCT02065791. PODCAST/UNASSIGNED:This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.

PURPOSE OF REVIEW/OBJECTIVE:Several nontraditional risk factors have been the focus of research in an attempt to understand the disproportionately high cardiovascular morbidity and mortality in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) populations. One such category of risk factors is cardiovascular autonomic dysfunction. Its true prevalence in the CKD/ESKD population is unknown but existing evidence suggests it is common. Due to lack of standardized diagnostic and treatment options, this condition remains undiagnosed and untreated in many patients. In this review, we discuss current evidence pointing toward the role of autonomic nervous system (ANS) dysfunction in CKD, building off of crucial historical evidence and thereby highlighting the areas in need for future research interest. RECENT FINDINGS/RESULTS:There are several key mediators and pathways leading to cardiovascular autonomic dysfunction in CKD and ESKD. We review studies exploring the mechanisms involved and discuss the current measurement tools and indices to evaluate the ANS and their pitfalls. There is a strong line of evidence establishing the temporal sequence of worsening autonomic function and kidney function and vice versa. Evidence linking ANS dysfunction and arrhythmia, sudden cardiac death, intradialytic hypotension, heart failure and hypertension are discussed. SUMMARY/CONCLUSIONS:There is a need for early recognition and referral of CKD and ESKD patients suspected of cardiovascular ANS dysfunction to prevent the downstream effects described in this review.There are many unknowns in this area and a clear need for further research.